TY - JOUR
T1 - Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice
AU - Fernández-Barrena, Maite G.
AU - Monte, Maria J.
AU - Latasa, Maria U.
AU - Uriarte, Iker
AU - Vicente, Eva
AU - Chang, Haisul C. Y.
AU - Rodriguez-Ortigosa, Carlos M.
AU - Elferink, Ronald Oude
AU - Berasain, Carmen
AU - Marin, Jose J. G.
AU - Prieto, Jesus
AU - Ávila, Matias A.
PY - 2012
Y1 - 2012
N2 - Background & Aims: Bile acids (BA) are increasingly recognized as important modulators of liver regeneration. Increased enterohepatic BA flux has been proposed to generate specific signals that activate hepatocyte proliferation after partial hepatectomy (PH). We have investigated the role of the BA membrane transporter Mrp3 (Abcc3), which is expressed in the liver and gut, in the hepatic growth response elicited by BA and in liver regeneration after PH. Methods: Liver growth and regeneration, and the expression of growth-related genes, were studied in and Mrp3(-/-) mice fed a cholic acid (CA) supplemented diet and after 2/3 PH. Activation of the BA receptor FXR was measured in mice after in vivo transduction of the liver with a FXR-Luciferase reporter plasmid. BA levels were measured in portal serum and liver tissue by high performance liquid chromatography-tandem mass spectrometry. Results: Liver growth elicited by CA feeding was significantly reduced in Mrp3(-/-) mice. These animals showed reduced FXR activation in the liver after CA administration and decreased portal serum levels of BA. Liver regeneration after PH was significantly delayed in Mrp3-deficient mice. Proliferation-related gene expression and peak DNA synthesis in Mrp3(-/-) mice occurred later than in wild types, coinciding with a retarded elevation in intra-hepatic BA levels. Conclusions: Lack of Abcc3 expression markedly impairs liver growth in response to BA and after PH. Our data suggest that Mrp3 plays a non-redundant role in the regulation of BA flux during liver regeneration. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved
AB - Background & Aims: Bile acids (BA) are increasingly recognized as important modulators of liver regeneration. Increased enterohepatic BA flux has been proposed to generate specific signals that activate hepatocyte proliferation after partial hepatectomy (PH). We have investigated the role of the BA membrane transporter Mrp3 (Abcc3), which is expressed in the liver and gut, in the hepatic growth response elicited by BA and in liver regeneration after PH. Methods: Liver growth and regeneration, and the expression of growth-related genes, were studied in and Mrp3(-/-) mice fed a cholic acid (CA) supplemented diet and after 2/3 PH. Activation of the BA receptor FXR was measured in mice after in vivo transduction of the liver with a FXR-Luciferase reporter plasmid. BA levels were measured in portal serum and liver tissue by high performance liquid chromatography-tandem mass spectrometry. Results: Liver growth elicited by CA feeding was significantly reduced in Mrp3(-/-) mice. These animals showed reduced FXR activation in the liver after CA administration and decreased portal serum levels of BA. Liver regeneration after PH was significantly delayed in Mrp3-deficient mice. Proliferation-related gene expression and peak DNA synthesis in Mrp3(-/-) mice occurred later than in wild types, coinciding with a retarded elevation in intra-hepatic BA levels. Conclusions: Lack of Abcc3 expression markedly impairs liver growth in response to BA and after PH. Our data suggest that Mrp3 plays a non-redundant role in the regulation of BA flux during liver regeneration. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved
U2 - https://doi.org/10.1016/j.jhep.2011.05.031
DO - https://doi.org/10.1016/j.jhep.2011.05.031
M3 - Article
C2 - 21756856
SN - 0168-8278
VL - 56
SP - 367
EP - 373
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -